The Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP AF) Clinical Trial: Interview with Kevin Wheelan, MD

What is the purpose of the STOP AF trial? Describe the trial objectives. What is important about STOP AF is that it is the first trial designed to obtain FDA approval for a catheter-based treatment for atrial fibrillation. Although the area of AF ablation has grown tremendously over the past 5 or 6 years, all of it has been based on radiofrequency catheter ablation, which has evolved from treatment of many other types of arrhythmias. None of the catheters that we currently use are actually approved for atrial fibrillation ablation by the FDA; they are used off label. This is a pivotal trial in that it is the first time that the FDA has dealt with the issue of defining the success of catheter-based ablation approaches to atrial fibrillation. STOP AF has a rigorous all or none endpoint of any documented AF as a failure in either the medical or balloon treatment arms. The objective of the trial is to prove that cryoablation of the PV ostium is better than medical therapy in patients with idiopathic paroxysmal atrial fibrillation. The endpoint of the study is the elimination of spontaneous AF at one year. The secondary endpoints of the trial are symptomatic improvement, reduction in frequency of the episodes, differences in incidence of hospitalizations or need for cardioversion, etc. Most importantly, the primary goal of the trial is to statistically prove that the catheter cryoablation technique is as safe as medication, but offers improved efficacy. What is the target patient population for the study? How many sites are participating? There are a total of 22 North American sites. STOP AF is a randomized controlled trial, with a 2:1 randomization; this means that 2 patients will receive cryoablation and 1 patient will receive medication. This design is predicated on statistical modeling designed to prove or disprove the study hypothesis that ablation is equal to or better than medication for prevention of AF. The medication (or control) group will receive 1 of 3 different antiarrhythmic drugs flecainide, propafenone or sotalol. The study design is for a total of 243 patients, with 12 months of follow up. There is also the opportunity of crossover from the drugs to the cryo treatment arm at 6 months. The specific target population is patients with idiopathic paroxysmal atrial fibrillation, defined as 2 or more episodes of AF during the 2 months preceding enrollment, at least 1 of which must be documented by EKG. Patients are only allowed mild structural heart disease. The age range is 18-75 years old, and these patients have to have failed at least 1 primary antiarrhythmic drug in the past (see website for details of inclusion/exclusion criteria). Tell us about the Arctic Front ® balloon, including size options, diameter, FlexCath interoperability, etc. The Arctic Front cryoballoon (CryoCath Technologies, Inc., Montreal, Quebec, Canada), as it is currently configured, is available in 2 sizes: 23 mm and 28 mm with an inner lumen for wire manipulation. It is predominantly a spherical design balloon, with an added safety feature in that there is an inner balloon and an outer balloon. The outer balloon maintains a constant vacuum, so in the event that any leaks should occur, none of the liquid Nitrous Oxide would come in contact with the patient. The delivery system includes a 14 French steerable sheath, and from my experience, the steerable balloon platform is well designed and very robust to maneuver in the left atrium and occlude the pulmonary veins. I am also impressed by its effectiveness in isolating the targeted pulmonary veins. How does the Arctic Front balloon treat atrial fibrillation? What unmet need will the Arctic Front balloon help fulfill? The goal of this trial is to create complete isolation of all 4 of the pulmonary veins (or their branches). However, as we know, sometimes the right side (more often than the left) of the veins may have a middle vein, so you might have 3 different discreet vein ostia there. In order to be classified as successful according to the protocol, we must isolate at least 3 of the pulmonary veins (2 superiors and 1 inferior). Patients receive a CT, angiography or MRI scan ahead of time, which defines their pulmonary venous anatomy. During the procedure, we ll use intracardiac echo, angiography, and the CT scan or MRI to determine optimal sizing of which balloon we want to use. More commonly we have been using the larger size balloon and reserving the smaller balloon only for those veins that cannot be isolated with the 28 mm balloon. We are finding that by being more proximal in what we would call the ‘vein antrum, rather than inside the actual os of the vein, we are getting a larger surface area of freeze, and I believe a better degree of isolation and elimination of the substrate that is causing AF in this population of patients. What advantages does the Arctic Front balloon offer over current treatments for AF? Currently there are some surgical and catheter-based options that are clinically available for patients. Of the catheter-based strategies, the primary approach that is being used worldwide is radiofrequency energy. There is a wide range of catheters; most physicians who do this procedure use either an 8 mm tip or an irrigated tip 4 mm catheter to ablate in the left atrium. The cryocatheter, a steerable EP catheter with a defined tip electrode for cryoablation purposes, is most commonly used in the 6 mm or 8 mm size. With cryoablation you have the ability to spot freeze, and this can be especially helpful in AVNRT cases; however, when it comes to treating atrial fibrillation, point-by-point freezing is really not being used as a primary modality, because it takes too long. The advantage in using the cryoballoon is that it allows you to create an entire circumferential freeze with 1 application that lasts 4 minutes. There are other research protocols taking place. One is a high intensity ultrasound catheter that is designed to disrupt tissue by beaming high energy ultrasound signals into the targeted zone of tissue and destroying them, but that trial s technology has been met with some problems and is moving forward slowly. More recently, another trial has gotten underway using a laser-based approach to target the application of energy at the mouth of the pulmonary veins to create ablative lesions. This trial is still at an early stage. How will this technology impact both AF patients and the physicians who treat them? I believe this is highly dependent on what the results of this study are. Currently this technology is market-approved in Europe, and if one looks at the rate of adoption and the growth occurring among our European colleagues, I predict there will be a very significant and rapid adoption of this technology in the United States. This is all contingent upon the results of this trial proving to be positive. The European data which has been presented indicates that there is at least an 80% effectiveness rate with cryoablation for this subgroup of paroxysmal AF patients, and there has also been some recent abstract data suggesting it may have a role in persistent AF patients as well. If the U.S. trial comes to the same conclusions as the European data, I personally think there will be a radical paradigm shift in the electrophysiology lab, because cryoablation has less risk of death and serious complications than radiofrequency ablation. Esophageal perforation has not been seen with cryoablation. In addition, pulmonary vein stenosis, which is another very difficult to treat problem that can occur with radiofrequency ablation, has not been seen with cryoablation. Although the mechanics of performing the procedure can be associated with certain complications, the more serious and difficult to manage complications do not appear to be occurring with cryo. Having said that, there is a risk of injury to the right phrenic nerve due to the proximity of the nerve to the right superior pulmonary vein. Freeze-induced palsy of that nerve can occur, as with other technologies. To mitigate the risk of damaging the phrenic nerve, we typically choose the larger 28 mm balloon and keep the balloon positioned as proximal as possible, and we continuously pace the phrenic nerve during any ablations that are in close proximity to the phrenic nerve. Nerve tissue also typically recovers well after freeze injury. I think the bottom line here is the potential simplicity of the procedure: by doing only a modest number of cryoapplications, one can get complete isolation of all 4 of the pulmonary veins in a very high percentage of patients. While it does require a considerable amount of operator skill in terms of performing a transseptal and manipulating catheters in the left atrium, I believe that the skill level is less than what is necessitated by some of the RF techniques, and certainly on a time basis, cryoablation techniques should allow the procedure to be performed much more rapidly simply because of the ability to cover larger areas and isolate a complete vein with perhaps as little as 1 or 2 applications of cryo energy. Ultimately, I believe we are on the cusp of a new technology. Hopefully balloon design enhancements will facilitate an even better balloon/vein interface for patients with challenging anatomies. Some patients have a common vein ostium that is larger than the 28 mm balloon. There are some unique challenges, but they are not insurmountable. How is the STOP AF trial different from other balloon and AF trials? Let s focus on cryo, because there are other balloons that have been used as part of the vehicle for delivering energy. One of the ongoing trials using laser has a balloon as an integral part of the system, and the high frequency ultrasound also has a balloon as a component of the system; the difference is that in the case of cryo, the balloon itself is the delivery tool that is what creates the freeze. Thus, the way that balloon interacts with the mouth of the pulmonary vein and the operator s ability to create an occlusive seal to wedge the balloon up into the vein and produce a complete circumferential freeze is key to achieving a high degree of success with this technique. I believe other cryoballoons have been designed, although I m not sure if any of those have progressed into human trials, and some of them have had problems with deployment and redeployment (i.e., pumping liquid nitrogen into the balloon, getting it back to the console, collapsing the balloon, and allowing it to be relatively easily manipulated to other vein locations in the atrium). This is the first product that I m aware of where all of those elements have come together in a system that can be successfully used in people. What is the completion date for this trial? The completion date depends upon investigator enrollment. The company hoped that enrollment would be finished by the end of calendar year 2007; however, this is a complex protocol, and enrollment has been slower than predicted. It will take a year of follow up (after the last patient completes his follow up) until there is a complete data set to go to the FDA with for PMA approval. I would estimate that by early spring there is a good likelihood that all the patients will have been enrolled, and then we would have to wait for the follow up data to be collected. Therefore, it s a product that the general electrophysiologist might not see available until potentially a couple of years. How can a doctor get a patient enrolled in this trial? In addition, how can a patient interested in the trial get information? The best way is for the physician to visit CryoCath s website (www.cryo-cath.com) and click on the link to the STOP AF trial. There is a listing of the participating centers and the appropriate individuals to contact. There are centers all around the country that are offering this enrollment to their patients. Patients can also visit the website to get a trial description and a complete list of participating centers and contact information. Is there anything else you d like to add? This is a dramatically innovative product that may revolutionize how we in the electrophysiology lab manage AF patients. I don t think that paradigm is fully understood by many people, simply because the awareness of the data concerning Arctic Front and cryoablation hasn t fully gotten out there. Although there are several hundred European patients who have been successfully treated at this time, there hasn t been a large clinical trial such as this for the U.S. population. For someone like me, who runs an electrophysiology lab and has been doing AF ablation ever since 1999, it is incredibly exciting to use technology that has the potential to cure a very high percentage of patients. We ve come to expect 95% success rates or greater with conventional ablations (e.g., AV node tachycardia or accessory pathways), and yet the field of atrial fibrillation has been very frustrating with success rates that can range anywhere from 50% up to 85%. A lot of this is because of the different subgroups of AF patients paroxysmal, persistent and chronic. Having technology that levels that playing field and takes the average electrophysiologist and lets them become proficient at AF ablation is exciting. AF ablation is predominantly available now only in specialized centers, by electrophysiologists who have dedicated a significant amount of time learning the RF technique. Projecting forward into the future, I believe what we ll see are hybridizations in which the Arctic Front approach of using a cryoballoon to create isolation of the pulmonary veins is done, and then concomitant with that, utilization of other ablative tools to create linear lines or perform adjunctive strategies such as fractionated potential ablation to deal with patients who have more persistent or permanent AF. In the end, the future is very exciting for this technology. For more information about the STOP AF trial, please visit: www.cryocath.com